Despite decades of basic and clinical research, cancer remains one of mankind's greatest scourges. According to statistics collected by the World Health Organization, cancer is one of the leading causes of death worldwide, having killed 7.4 million people in 2004, or about 13% of all deaths that year. While much has been learned regarding what causes cancer, and how cancer works at the molecular level, the greatest reductions in cancer death rates remain attributable to public health interventions, such as anti-smoking campaigns, and earlier diagnosis made possible by advances in imaging technology and molecular diagnostics. When it comes to the hard work of actually killing cancer cells, however, clinicians still rely on therapeutic modalities, such as surgery, radiation and chemotherapy, that would have been familiar to oncologists of a generation ago. Although the efficacy of all these treatments has improved over the years, the improvement in cure rates and the increase in longevity has been incremental. Even the new targeted therapies resulting from the revolution in molecular oncology have, for the most part, improved outcomes modestly.
Pancreatic cancer, a malignant neoplasm of the pancreas, is a particularly challenging form of cancer to treat, as it typically goes undetected until no longer treatable ((Jemal et al., 2008, CA Cancer J. Clin. 58(2):71-96)). The prognosis is poor-fewer than 5% of those diagnosed with pancreatic cancer are still alive 5 years after diagnosis ((Jemal et al., 2010, CA Cancer J. Clin. 60(5):277-300)), and complete remission is rare ((Ghaneh et al., 2007, Gut 56(8):1134-1152)). The median survival from diagnosis is only 3-6 months ((Stathis & Moore, 2010, Nat. Rev. Clin. Oncol. 7(3):163-172)). It has been estimated that in 2010, about 43,000 individuals in the United States alone will be diagnosed with pancreatic cancer, and that about 36,800 will die from the disease (see, www.cancer.gov/cancertopics/types/pancreatic). Although pancreatic cancer accounts for only 2.5% of new cancer cases diagnosed each year, it is responsible for 6% of yearly cancer deaths ((Jemal et al., 2007, Cancer J. Clin. 57(1):43-46)), representing one of the highest fatality rates of all cancers. Indeed, in the United States, pancreatic cancer is the fourth-highest cancer killer amongst men and women.
Another challenging aspect of managing cancer is treating patients in whom cells from the primary (original) tumor have broken free and migrated to another location within the body, typically through the lymph or blood, via a process called “metastasis,” to form another, metastatic (or secondary) tumor. The secondary or metastatic tumor is typically of the same type as the original tumor, regardless of its new location, such that the disease is referred to as metastatic cancer, and not cancer of the new resident tissue. For example, pancreatic cancer that has spread to the liver is metastatic pancreatic cancer, not liver cancer. Since primary pancreatic cancer is often not diagnosed until a late stage, the incidence of metastasis is high. Indeed, approximately 80% of patients already have metastasis at the time of diagnosis ((Sohn et al., 2000, J. Gastrointest. Surg. 4(6):567-579)).
Metastasis limits treatment options, as resection or removal of the primary tumor is no longer a sufficient treatment option. Gemcitabine-based chemotherapy currently represents the standard of care for any patient with metastatic disease. Survival of patients with metastatic disease treated with gemcitabine is only about 6 months (ranging from 4.0 to 7.1 months, depending upon the study). Current trials with combination treatments, for example gemcitabine with chemotherapy (oxaliplatine, 5-FU or irinotecan), or gemcitabine with targeted therapy (erlontinib, bevacizumab or cetuximab) report only a 1 to 2 month gain in survival ((Sathis & Moore, 2000, Nat. Rev. Clin. Oncol. 7(3):163-172)).
While moderate advances in the treatment options for primary pancreatic cancer and metastatic pancreatic cancer have been made in recent years (see, Id.), there remains a pressing need for alternative and/or more effective therapies.